Presently, there exists no simple minimally invasive test, such as a blood test, that can differentiate patients affected by Alzheimer's disease (AD) from healthy individuals. Our long-term goal is to develop new strategies for determining prognosis or predicting response to therapy. This will provide tools to improve clinical decision-making in the care of AD patients. It will also encourage individuals to test for AD early thereby maximizing opportunities for successful treatment. Our specific hypothesis is that patients with increased oxidative stress in the brain, such as AD patients, should have depleted levels of the DHEA precursor. Thus, plasma samples should contain limited levels of DHEA precursor to form DHEA in response to Fe ++ treatment. We base our hypothesis on the observations that: (1) Brain cells convert cholesterol to pregnenolone, precursor of a number of steroid modulators of neuronal functions, including DHEA, (2) DHEA biosynthesis is mediated by a cytochrome P450 17 (-hydroxylase (P450c17)-independent mechanism involving a yet unidentified hydroperoxide precursor, (3) This pathway is regulated by agents, such as Fe ++ and B-amyloid (AB) peptide, (4) DHEA levels are elevated in AD brain tissue specimens and it is formed in the AD brain by the oxidative stress-mediated metabolism of an hydroxyperoxy-steroid precursor, thus depleting the levels of the precursor present in plasma. Our specific aims are to: (1) Differentiate between the levels of DHEA precursor in the plasma of patients with AD and normal individuals. We will test for the presence of DHEA precursor in human plasma using a simple Fe ++ -based reaction and determine the amounts of DHEA formed. This simple chemical reaction will be followed by a specific and sensitive capillary gas chromatography/mass spectrometric methodology for the quantitative determination of DHEA. (2) Define the relationship between the levels of DHEA precursor in plasma and AD. We expect that the absence of the precursor in the plasma would correlate with the levels of brain oxidative stress and cognitive measures (MMSE). Should we demonstrate the DHEA precursor correlation, we can provide an early warning of oxidative stress mediated pathology, such as AD. In this Phase I application we propose to test this hypothesis in a small number of samples obtained from AD and control (non-demented) patients.